ABSTRACT Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) affecting an estimated 2.5 million people worldwide. Recent work strongly implicates the innate immune system in the development of both MS and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). C-type Lectin Receptors (CLR) are a major class of pattern recognition receptors (PRR) that can initiate innate immune responses, but their role in autoimmune disease and in MS is largely unknown. My preliminary data demonstrates that the CLR dectin-1 has an unexpected protective role in EAE. Mice lacking dectin-1 develop more severe EAE, and a single injection of a dectin-1 agonist can reduce disease incidence and severity. The primary objective of this project is to dissect the mechanisms by which dectin-1 signaling is protective in CNS autoimmune disease, using EAE as a model. Recently, I found that dectin-1 signaling can upregulate the neuroprotective factor, Oncostatin M (Osm) in myeloid cells. Based on my preliminary data, this upregulation appears to occur through a non-canonical dectin-1 signaling pathway independent of CARD9 and RAF1. Additionally, I found that a recently identified endogenous ligand for dectin-1 is upregulated in EAE and can similarly induce Osm. In this proposal, I will determine the cell subsets and ligands responsible for protective dectin-1 signaling and I will uncover the mechanism and function of dectin-1 induced Osm in EAE. By identifying and dissecting protective innate immune signaling by dectin-1 in EAE, this research has the potential to reveal novel targets for immunotherapy in MS.